A lack of non-invasive and molecular-specific biomarkers to detect cartilage degradation has prevented a fundamental understanding of the development of osteoarthritis (OA), as well as early diagnosis of and intervention in OA. Unlike conventional Magnetic Resonance Imaging (MRI) that monitors image intensity or area/volume, Microscopic MRI (uMRI) is well-suited for the quantitative study of articular cartilage. MRI can produce 2D and 3D images not only of water distribution, but also of unique parameters reflecting the molecular environment in the tissue at microscopic resolution. In our current studies of cartilage, we have used the histology gold-standard, polarized light microscopy (PLM), to validate the 14um-resolution uMRI results. We demonstrate that the magic-angle imaging via T2- anisotropy in uMRI can examine the ultrastructural properties in individual histological zones in cartilage with high sensitivity and molecular specificity. This proposal has five Specific Aims. Aims 1-3 study the anisotropy ! distribution / interactions of three major molecular components in cartilage (collagen fibrils, proteoglycans, water) at microscopic resolution. Aim 4 extends the microscopic study of tissue blocks to the study of intact whole joint at intermediate resolution. Aim 5 extends the imaging study further into the clinical application using a whole-body MRI scanner. In combination, these five aims will yield otherwise unavailable new information to elucidate nondestructively various biophysical, biochemical and biological mechanisms and properties in this important biomaterial. Our proposal is unique in combining quantitative and microscopic imaging techniques (uMRI, PLM, electron microscopy, Fourier-transform infrared imaging), spatially-resolved molecular-specific markers, and histological details. In view of complicated molecular changes due to osteoarthritis and the interdependent structure-function relationships exhibited by macromolecules in tissue, our multi-disciplinary approach can discriminate among the various possible biochemical and ultrastructural states and their influence on the functional integrity of the tissue. We aim (1) to characterize the properties of both healthy and lesioned tissues quantitatively, and (2) to determine a set of baselines ! guidelines for the successful clinical application of T2 anisotropy imaging, thus providing critical information towards the understanding, and ultimately, prevention of arthritic diseases.